Pneumocystis remains a common infection in patients with deficient CD4+ T-cell function. Analysis of murine and human models of the infection has revealed a critical for IL-21R, STAT3 signaling CD4+ T-cells as well as CD209 expressing macrophages. These data lead us to propose the hypothesis that IL-21R and STAT3 are required in a CD4+ T cell autonomous way to mount anti-Pneumocystis effector responses in the lung. Moreover we hypothesize that a major effector pathway regulated by this pathway is the recruitment of GM- CSFR+, high mannan binding (via expression of CD209 isoforms) and ?1,3 glucan binding (via Dectin-1) macrophages that mediate fungal clearance. We will test this hypothesis with the following Aims: Specific Aim 1. Test the prediction that IL-21R and STAT3 are required in CD4+ T-cells to mediate resistance to Pneumocystis infection. Specific Aim 2. Test the prediction that IL-21R and STAT3 control GM-CSF production which is critical for recruitment of fungicidal macrophages and fungal clearance. Specific Aim 3. Test the prediction that CD4+ T-cells as well as IL-21R signaling facilitate fungal clearance by regulating the recruitment of fungicidal macrophage population that express GM-CSF receptors and c-type lectin receptors that bind and internalize fungi, namely Dectin-1 and CD209. These studies will be carried out in murine studies as well as translational human studies and will increase our understanding of the pathogeneses of this infection that will lead to new therapeutic and preventive strategies.